CN108057064B - Corydalis tuber total alkaloid gastric floating tablet - Google Patents
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Abstract
The invention relates to the field of traditional Chinese medicine preparations, and discloses a corydalis tuber total alkaloid gastric floating tablet which comprises an active ingredient and pharmaceutic adjuvants, wherein the active ingredient is an extract of corydalis tuber total alkaloid, and the pharmaceutic adjuvants comprise a sustained-release framework material, a retardant, a bleaching aid and a glidant; the weight ratio of the active ingredients to the pharmaceutical excipients is 1: 1.1-1: 2.1. The gastric floating tablet prepared by the invention has quick floating time, long lasting floating time and slow release function; after administration, the gastric floating tablet can form gel adhesion with water by virtue of its floatability, so that it is not affected by gastric emptying, can be retained in stomach for a long time, and has high bioavailability, strong drug effect, small local irritation, and greatly improved patient compliance.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine preparations, in particular to corydalis tuber total alkaloid gastric floating tablets.
Background
The traditional Chinese medicine rhizoma Corydalis is a dried tuber of Corydalis yanhusuo W.T.Wang (Corydalis yanhusuo) of Papaveraceae, has the effects of promoting blood circulation, benefiting qi and relieving pain, is used for treating chest and hypochondrium, abdominal pain, traumatic swelling and pain and the like, and is a famous analgesic which is advocated by traditional Chinese medical scientists all the time. Li Shizhen describes Yan Hu Suan in Ben Cao gang mu: ' specially treating all pains of the upper and lower parts of the body, especially for the middle-jiao and the superficiality, covering Yanhusuo to activate blood and transform qi, the first herb is also included. Therefore, the corydalis tuber has a long history and a good application prospect in analgesia.
Because of the good analgesic effect of corydalis tuber, at present, various corydalis tuber preparations are on the market, such as corydalis tuber analgesic tablets, corydalis tuber analgesic capsules, corydalis tuber analgesic granules, corydalis tuber analgesic dispersible tablets, corydalis tuber analgesic dropping pills, compound corydalis tuber analgesic tablets, compound corydalis tuber aluminum hydroxide rotundine, corydalis sulfate ethyl tablets, compound corydalis tuber spray and the like. However, the preparation has the defects of large administration dosage, frequent administration times, easy occurrence of peak-valley phenomenon of blood concentration and the like. The corydalis tuber preparation is a normal-release preparation formulation, a patient needs to take multiple times of administration to achieve a good analgesic effect, and the compliance of the patient has certain problems.
The patent with the application number of CN201210464758.1 discloses a preparation method of non-alkaloid pills extracted from szechwan chinaberry fruit and corydalis tuber for treating gastric ulcer, which relates to a preparation method of non-alkaloid pills extracted from szechwan chinaberry fruit and corydalis tuber. The traditional Chinese medicine Jinling powder is used for solving the problems that the existing western medicines for treating gastric ulcer have side effects, and the traditional Chinese medicine Jinling powder is inconvenient to take and large in dosage. The method comprises the following steps: firstly, mixing rhizoma corydalis and szechwan chinaberry fruit, and carrying out water extraction; secondly, carrying out alcohol extraction on the concentrated solution to obtain neutral ion exchange solution containing non-alkaloid components; thirdly, concentrating the neutral ion exchange liquid containing the non-alkaloid components to obtain non-alkaloid paste, and drying to obtain non-alkaloid powder; fourthly, preparing the non-alkaloid powder, the starch and the purified water into pills, thus completing the preparation. The invention has the advantages of stable medicinal components, lower cost, convenient use and better curative effect. The effect of treating the ulcer is equivalent to that of a typical western medicine omeprazole for treating gastric ulcer; compared with the fructus toosendan powder, the fructus toosendan powder is more convenient to take and has small dosage. Said patent utilizes corydalis tuber to cure stomachache, and adopts the conventional release preparation technology, and its retention time in stomach is short, and it needs frequent administration to retain medicinal effect.
Disclosure of Invention
In order to solve the technical problems, the invention provides the corydalis tuber total alkaloid gastric-floating tablet which has the advantages of quick floating time, long lasting floating time, slow release effect, high bioavailability, strong drug effect and small local irritation.
The specific technical scheme of the invention is as follows: a rhizoma corydalis total alkaloids gastric floating tablet comprises active ingredient and pharmaceutical adjuvant, wherein the active ingredient is rhizoma corydalis total alkaloids extract, and the pharmaceutical adjuvant comprises sustained release skeleton material, blocker, bleaching aid and glidant; the weight ratio of the active ingredients to the pharmaceutic adjuvants is 1: 1.1-1: 2.1.
At present, no gastric floating tablet product related to corydalis tuber exists in the prior art, and the gastric floating tablet can greatly delay the release of the medicine, prolong the medicine effect and reduce the medicine taking times; stable and lasting effective blood concentration is provided, and adverse reaction is reduced; the medicine is retained in the stomach for a long time, and has special significance for treating diseases (such as epigastric pain and the like) of some special parts. The corydalis tuber is prepared into the gastric floating tablets, meets the advantages of the dosage forms, and is favorable for better exerting the treatment effect on epigastric pain.
In addition, the invention uses the traditional Chinese medicine material group as a whole to visually evaluate the release performance of the corydalis ambigua total alkaloid gastric-floating tablets. The research reports of the corydalis tuber sustained and controlled release preparation are increased year by year, but the single or multiple index components are mostly adopted to evaluate the release rate of the traditional Chinese medicine sustained and controlled release preparation, and the single or multiple index components cannot represent the characteristics of multi-component and integral action of the traditional Chinese medicine. The invention creatively utilizes the integral theoretical system of the traditional Chinese medicine and the method of the substance group to analyze the release condition of the traditional Chinese medicine on the whole. The basic meaning of the group of substances of Chinese herbs is the collection of all components contained in a unit Chinese herb or an important compound preparation, which are dissolved in a medium (the medium in oral administration is gastrointestinal fluid). According to the invention, at different time points, the dissolution liquid of the adhesive sheet floating in the stomach is scanned within the range of 220-400 nm by an ultraviolet spectrophotometer, and data processing, analysis and fitting are carried out by using corresponding substance group software to obtain the release amount and release increment of the preparation at each time point, so that the release performance of the bulk drug can be integrally and visually evaluated, the bulk drug is in accordance with the integral view of the traditional Chinese medicine, and the method has a certain significance.
Preferably, the corydalis tuber total alkaloid gastric floating tablets comprise the following components in percentage by weight:
32 to 47 percent of rhizoma corydalis total alkaloid extract;
24-33% of a slow-release framework material;
12-29% of a retarder;
9-26% of bleaching assistant;
0.8-1.2% of glidant.
Preferably, the main active ingredients in the rhizoma corydalis total alkaloid extract comprise palmatine hydrochloride, dehydrocorydaline, tetrahydropalmatine and corydaline A, the proportion of the four monomeric alkaloids in the rhizoma corydalis total alkaloid (the content is 100%) is 1: 5.96-7.63: 2.46-2.86: 2.92-3.46, the content of the total alkaloid in the rhizoma corydalis total alkaloid extract is measured by an acid dye colorimetric method, and the purity of the rhizoma corydalis total alkaloid is 60-80% measured at 411nm of a visible spectrophotometer.
Preferably, the slow release framework material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose and sodium alginate.
Preferably, the retarder is one or more of octadecanol, ethyl cellulose and acrylic resin.
Preferably, the bleaching aid is one or more of calcium bicarbonate, sodium bicarbonate and magnesium carbonate.
Preferably, the glidant is selected from one or more of magnesium stearate, aerosil and talcum powder.
The preparation method of the rhizoma corydalis total alkaloid extract comprises the following steps:
(1) extracting rhizoma corydalis decoction pieces with ethanol to obtain extractive solution;
(2) concentrating the extractive solution until no alcohol smell is present, centrifuging, and collecting supernatant to obtain supernatant.
(3) Loading the pretreated macroporous resin into a column, loading the sample, and removing impurities;
(4) eluting with an eluting solvent, and collecting the eluent after discarding the previous 0.5-1.5BV of eluent.
In the prior art, all of the eluate is collected. However, the present inventors have discovered that, by chance, the purity of the eluate can be significantly improved by discarding a part of the eluate at the early stage. After subsequent researches, the reason is that after the elution solvent is added, part of the impurity-removing solvent remains in the chromatographic column, and at the moment, the elution is mainly non-alkaloid impurities, so that the elution is formally collected after being discarded, and the purity is favorably improved.
(5) Concentrating the collected eluent, and drying to obtain the final product.
The invention provides a new scheme for extracting rhizoma corydalis total alkaloids and improving the purity and transfer rate of the rhizoma corydalis total alkaloids, which mainly extracts alkaloid effective components in traditional Chinese medicine rhizoma corydalis to a greater extent, removes impurities such as starch, mucilage, resin, volatile oil and the like in the extract by a purification method, solves the problems of low purity and low conversion rate of the total alkaloids, and optimizes the total process by taking four alkaloid monomers as indexes to maximize the purity of the total alkaloids and the four alkaloid monomers. Meanwhile, the drug effect of the rhizoma corydalis purified product is explored from the analgesic perspective, and a reference basis is provided for developing rhizoma corydalis total alkaloid analgesic drugs.
The invention not only takes the content of the total alkaloid of corydalis tuber as an index, but also takes the content of the total alkaloid of corydalis tuber and four alkaloid monomers as indexes to investigate the extraction, purification, concentration and drying processes. Looking up published documents and patents, the process optimization is basically carried out by using the total alkaloids from corydalis tuber, tetrahydropalmatine or other single indexes, and the process optimization and screening are not carried out by using the contents of the total alkaloids from corydalis tuber and four alkaloid monomers as indexes.
The corydalis total alkaloid in the corydalis total alkaloid extract is calculated by tetrahydropalmatine, and the purity is as follows: 60-80%. The ratio of the four monomeric alkaloids in the total alkaloids of the corydalis tuber (the content is 100 percent) is 1: 5.96-7.63: 2.46-2.86: 2.92-3.46, the transfer rate of the total alkaloids of the corydalis tuber is more than 85 percent, and the transfer rates of the four monomeric bases are all more than 95 percent. Compared with the prior art, the method makes remarkable progress.
Preferably, in the step (1), the extraction method comprises the following steps: carrying out reflux extraction on corydalis tuber decoction pieces for 1-3 times with ethanol with the mass of 8-12 times and the concentration of 55-65wt%, wherein the ethanol is used for 1.5-2.5 hours each time.
The inventor adopts a decoction method, a reflux extraction method and an ultrasonic extraction method in the test. The result shows that the reflux extraction method has the highest extraction rate of the total alkaloid of the corydalis tuber compared with a cold soaking method, a decoction method and an ultrasonic extraction method, and meets the aim of enriching the total alkaloid.
Through detection, the extracting solution obtained in the step (1) of the invention contains four alkaloids of palmatine hydrochloride, dehydrocorydaline, tetrahydropalmatine and corydaline A, and the purity is respectively as follows: 0.2-0.4%, 1.5-2.0%, 0.8-1.5%, 1.0-2.0%; the rhizoma corydalis total alkaloids in the obtained extracting solution have the following purity in terms of tetrahydropalmatine: 10.0 to 20.0 percent.
Preferably, in the step (2), the concentration conditions are as follows: concentrating at 50-60 ℃ until no alcohol smell exists; the centrifugation conditions were: centrifuging at 5000-; the concentration of the sample solution is 0.3-0.6 g crude drug/mL.
Part of impurities can be precipitated after the sample liquid is centrifuged, and when the supernatant liquid is taken for purification, the macroporous adsorption resin is not easy to agglomerate and block, so that the rhizoma corydalis total alkaloids can be better purified.
Preferably, in step (3), the macroporous adsorbent resin is XDA-8, NKA-9, D101, D141, HPD200A or AB-8.
Preferably, in the step (3), the column is packed by a wet method with the diameter-height ratio of 1: 5-1: 9, the sample loading amount is 1.5-2.3BV, the sample loading speed is 1.5-2.5 BV/h, and the standing is 1-2 h; the impurity removing solvent during impurity removing is one or more of ultrapure water, 0.1-0.3wt% NaCl solution or 8-12wt% ethanol solution; the dosage of the impurity removal solvent is 1.0-1.5 BV, and the impurity removal speed is 1.5-2.5 BV/h.
And standing after sampling is carried out, so that the rhizoma corydalis total alkaloids and the macroporous adsorption resin perform full action, the loss of alkaloids during impurity removal is reduced, and the purification effect is enhanced.
Preferably, in the step (4), the elution solvent is 80-95 wt% ethanol solution, the dosage of the elution solvent is 5.5-6.5 BV, and the elution speed is 2-4 BV/h.
Preferably, in the step (5), the eluent is firstly decompressed and concentrated at 55-65 ℃ until no alcohol smell exists, and then is spray-dried to obtain the alcohol-free water-soluble organic solvent; or concentrating the extract under reduced pressure to obtain a thick extract, and drying the thick extract in vacuum at the temperature of 55-65 ℃ to obtain the extract; or concentrating under reduced pressure to obtain a thick extract, and drying at the temperature of 55-65 ℃ under normal pressure to obtain the finished product.
In the prior art, the eluent is usually directly dried under normal pressure, dried in vacuum or spray-dried. However, the inventor finds that the drying is relatively quick under normal pressure, but the obtained extract is hard in texture and is not easy to collect; the vacuum-dried extractum is crisp in texture and easy to grind into powder, but the drying efficiency is too low; the spray drying has large loss amount due to wall sticking phenomenon, which causes the transfer rate of the rhizoma corydalis total alkaloids and the four monomeric bases to be reduced. Therefore, the invention creatively concentrates the eluent into thick extract under reduced pressure, then dries under normal pressure and finally dries in vacuum, thus solving the technical problem.
The invention also provides a preparation method of the corydalis tuber total alkaloid gastric floating tablet, which comprises the following steps: sieving rhizoma corydalis total alkaloids, sustained release skeleton material, retardant, bleaching agent and glidant with 60-100 mesh sieve, respectively, mixing by equivalent incremental method, and tabletting by dry method.
Compared with the prior art, the invention has the beneficial effects that:
1. the gastric floating tablet prepared by the invention can achieve good gastric retention and sustained release effects, and the curative effect is obviously superior to that of a common preparation. After administration, the gastric floating tablet has good floating performance (short floating time and long floating time) in gastric juice, and has gastric adhesion function after forming gel when meeting water, so that the gastric floating tablet is not influenced by gastric emptying and can be retained in the stomach for a long time; but also has good slow release effect (slow, lasting and complete drug release speed), can obviously increase the curative effect and avoid local irritation caused by overhigh drug concentration.
2. The invention discloses a method capable of efficiently extracting, purifying and transferring total alkaloids in traditional Chinese medicine rhizoma corydalis. The invention can separate and purify the high-purity total alkaloid (60-80%) from the corydalis tuber, the main active ingredients in the corydalis tuber total alkaloid extract comprise palmatine hydrochloride, dehydrocorydaline, tetrahydropalmatine and corydaline A, the purities of four monomeric bases in the extract are respectively 1.5-3.0%, 10.0-15.0%, 3.5-6.0% and 6.0-8.0%, the total alkaloid transfer rate is more than 85%, and the transfer rates of the four monomeric bases are all more than 95%, thereby solving the problems of low purity, low utilization rate and low treatment analgesic effect of the corydalis tuber total alkaloid and the four monomeric bases.
3. The preparation method of the corydalis tuber total alkaloid extract is simple and convenient to operate, and the obtained corydalis tuber total alkaloid is found through preliminary effectiveness test research to have better analgesic effect compared with tetrahydropalmatine, and is expected to improve the medicinal value of Zhejiang eight-flavor corydalis tuber.
Drawings
FIG. 1 shows the standard spectrum and blank auxiliary material spectrum of the concentration of total alkaloids from corydalis tuber in gastric floating tablets.
Detailed Description
The present invention will be further described with reference to the following examples.
General examples
A rhizoma corydalis total alkaloids gastric floating tablet comprises active ingredient and pharmaceutical adjuvant, wherein the active ingredient is rhizoma corydalis total alkaloids extract, and the pharmaceutical adjuvant comprises sustained release skeleton material, blocker, bleaching aid and glidant; the weight ratio of the active ingredients to the pharmaceutic adjuvants is 1: 1.1-1: 2.1.
Preferably, the corydalis tuber total alkaloid gastric floating tablets comprise the following components in percentage by weight:
32 to 47 percent of rhizoma corydalis total alkaloid extract;
24-33% of a slow-release framework material;
12-29% of a retarder;
9-26% of bleaching assistant;
0.8-1.2% of glidant.
Preferably, the main active ingredients in the rhizoma corydalis total alkaloid extract comprise palmatine hydrochloride, dehydrocorydaline, tetrahydropalmatine and corydaline A. The slow release framework material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose and sodium alginate. The retarder is one or more of octadecanol, ethyl cellulose and acrylic resin. The bleaching assistant is one or more of calcium bicarbonate, sodium bicarbonate and magnesium carbonate. The glidant is selected from one or more of magnesium stearate, aerosil and talcum powder.
A method for preparing rhizoma corydalis total alkaloid extract comprises the following steps:
(1) the extraction method comprises the following steps: carrying out reflux extraction on corydalis tuber decoction pieces for 1-3 times with ethanol with the mass of 8-12 times and the concentration of 55-65wt%, wherein the ethanol is used for 1.5-2.5 hours each time. Taking the extract.
(2) Concentrating the extractive solution under reduced pressure (50-60 deg.C, 50RPM) until no alcohol smell exists, centrifuging (5000-10000 RPM at 3-5 deg.C for 25-35 min), and collecting supernatant to obtain supernatant with concentration of 0.3-0.6 g crude drug/mL.
(3) And (3) filling the pretreated macroporous resin into a column by a wet method according to the diameter-height ratio of 1: 5-1: 9, adding a sample loading liquid (the sample loading amount is 1.5-2.3BV, the sample loading speed is 1.5-2.5 BV/h), standing for 1-2 h, removing impurities by using an impurity removal solvent, and removing the impurity removal liquid.
The impurity removal solvent is one or more of ultrapure water, 0.1-0.3wt% NaCl solution or 8-12wt% ethanol solution; the dosage of the impurity removal solvent is 1.0-1.5 BV, and the impurity removal speed is 1.5-2.5 BV/h.
(4) Eluting with eluting solvent, receiving the eluent from the beginning of adding eluting solvent, and collecting the eluent after discarding the first 0.5-1.5 BV.
Wherein the elution solvent is 80-95 wt% ethanol solution, the dosage of the elution solvent is 5.5-6.5 BV, and the elution speed is 2-4 BV/h.
(5) Concentrating the eluent under reduced pressure, concentrating the eluent under reduced pressure at 55-65 ℃ until no alcohol smell exists, and then spray-drying to obtain the compound preparation; or concentrating the extract under reduced pressure to obtain a thick extract, and drying the thick extract in vacuum at the temperature of 55-65 ℃ to obtain the extract; or concentrating under reduced pressure to obtain a thick extract, and drying at the temperature of 55-65 ℃ under normal pressure to obtain the finished product.
Example 1
A corydalis tuber total alkaloid gastric floating tablet is prepared by the following steps:
(1) preparing the rhizoma corydalis total alkaloid extract: reflux-extracting rhizoma corydalis decoction pieces with 60 wt% ethanol 8 times the weight of rhizoma corydalis decoction pieces for 3 times, each time for 2 hr. Taking the extract. Concentrating the extractive solution under reduced pressure (60 deg.C, 50RPM) until no alcohol smell exists, centrifuging (4 deg.C at 7000RPM for 30min), and collecting supernatant to obtain supernatant with concentration of 0.6g crude drug/mL. Loading macroporous resin into column at diameter-height ratio of 1: 6 by wet method, adding sample solution (sample amount of 2BV and sample speed of 2BV/h), standing for 2h, removing impurities with impurity removing solvent, and discarding impurity removing solution. Wherein, the pretreatment mode of the macroporous adsorption resin is as follows: soaking macroporous adsorbent resin with 2 times of ethanol with the mass of 95wt% for 24h, filtering, loading the resin on a column by a wet method, continuously washing with 95wt% ethanol at the flow rate of 2BV/h, washing until the eluent is clear after being mixed with distilled water with the flow rate of 1: 3, and then washing with distilled water at the same flow rate until no alcohol smell exists for later use. The impurity removal solvent is ultrapure water; the dosage of the impurity removal solvent is 1.0BV, and the impurity removal speed is 2 BV/h. Eluting with an eluting solvent, receiving the eluent from the beginning of adding the eluting solvent, and collecting the eluent after discarding the first 0.7BV of the eluent. Wherein the elution solvent is 95wt% ethanol solution, the dosage of the elution solvent is 6BV, and the elution speed is 2 BV/h. Concentrating the eluate under reduced pressure at 60 deg.C to obtain soft extract, drying at 60 deg.C under normal pressure, and vacuum drying at 60 deg.C. The prepared rhizoma corydalis total alkaloids have purity of 79.1% (rhizoma corydalis total alkaloids), 1.92% (palmatine hydrochloride), 14.65% (dehydrocorydaline), 4.94% (tetrahydropalmatine), and 6.33% (corydalis A).
(2) Preparing gastric floating tablets: weighing 15g of the corydalis ambigua total alkaloid extract, 8g of ethyl cellulose, 15M 12g of HPMC K, 8g of sodium bicarbonate, 3.2g of sodium alginate, 0.124g of silica gel micropowder and 0.25g of magnesium stearate according to a mass ratio, fully and uniformly mixing according to an equivalent incremental method, sieving and uniformly mixing, and directly tabletting powder with the hardness of 3-4 kg/m3 to obtain the corydalis ambigua total alkaloid gastric floating tablets, wherein the weight of each tablet is 2.5 +/-0.125 g.
The gastric floating tablet prepared by the method has the advantages of quick floating, long floating time (more than 12h), stable drug release, no burst release phenomenon (the cumulative release degree is 15% in 2h) and complete drug release (the cumulative release degree is 91% in 12 h).
Example 2
(1) Preparing the total alkaloid extract of corydalis root: weighing 50g of rhizoma corydalis decoction pieces, adding 10 times of 55% ethanol, and extracting under reflux for 1 time, each time for 2.5 hr. Mixing the obtained extractive solutions, concentrating under reduced pressure at 50 deg.C until no alcohol smell exists, centrifuging (3 deg.C at 5000rpm for 35min), and collecting supernatant to obtain supernatant with concentration of 0.3g crude drug/mL. Weighing the processed D141 resin (the diameter-height ratio is 1: 5), loading 1.5BV/h of a 1.5BV rhizoma corydalis extracting solution, standing for 1h, taking 1.5BV 10% ethanol solution as an impurity removal solvent, wherein the impurity removal speed is 2BV/h, taking 5.5BV 88% ethanol as an elution solvent, eluting at the speed of 2BV/h, collecting the eluent after discarding the former 0.5BV eluent, concentrating the eluent at 55 ℃ under reduced pressure to obtain a thick extract, drying at 55 ℃ under normal pressure, and finally drying at 55 ℃ under vacuum to obtain the D141 resin.
(2) Preparing gastric floating tablets: weighing 15g of the corydalis tuber total alkaloid extract, 8g of ethyl cellulose, 15g of HPMC K15M 8g, 8g of sodium bicarbonate, 3.2g of sodium alginate, 0.124g of superfine silica gel powder and 0.25g of magnesium stearate according to the mass ratio, fully and uniformly mixing according to an equivalent incremental method, sieving and uniformly mixing until the hardness is 3-4 kg/m3Directly tabletting the powder to obtain corydalis tuber total alkaloid gastric floating tablets, wherein the weight of each tablet is 2.5 +/-0.125 g.
The gastric floating tablet prepared by the method has the advantages of quick floating, long floating time (more than 12h), stable drug release, no burst release phenomenon (the cumulative release degree is 16% in 2h) and complete drug release (the cumulative release degree is 92% in 12 h).
Example 3
(1) Preparing the rhizoma corydalis total alkaloid extract: 50g of rhizoma corydalis decoction pieces are weighed, 12 times of 65% ethanol is added, and reflux extraction is carried out for 3 times, and each time lasts for 1.5 hours. Mixing the obtained extractive solutions, concentrating under reduced pressure at 60 deg.C until no alcohol smell exists, centrifuging (5 deg.C at 10000rpm for 25min), and collecting supernatant to obtain a supernatant as 0.6g crude drug/mL. Weighing the treated D141 resin (the diameter-height ratio is 1: 9), loading 2BV corydalis tuber extracting solution by a wet method, standing for 1.5h, taking 1.3BV ultrapure water as an impurity removal solvent, wherein the impurity removal speed is 2.5BV/h, taking 6BV 80% ethanol as an elution solvent, eluting at the speed of 3BV/h, collecting the eluent after discarding the former 0.5BV eluent, concentrating the eluent at 65 ℃ under reduced pressure to form thick extract, drying at 65 ℃ under normal pressure, and finally drying at 65 ℃ under vacuum to obtain the D141 resin.
(2) Preparing corydalis tuber total alkaloid gastric floating tablets: weighing 15g of the corydalis ambigua total alkaloid extract, 8g of ethyl cellulose, 15g of HPMC K15M 8, 12g of sodium bicarbonate, 3.2g of sodium alginate, 0.124g of silica gel micropowder and 0.25g of magnesium stearate according to a mass ratio, fully and uniformly mixing according to an equivalent incremental method, sieving and uniformly mixing, and directly tabletting powder with the hardness of 3-4 kg/m3 to obtain the corydalis ambigua total alkaloid gastric floating tablets, wherein the weight of each tablet is 2.5 +/-0.125 g.
The gastric floating tablet prepared by the method has the advantages of quick floating, long floating time (more than 12h), stable drug release, no burst release phenomenon (the cumulative release degree is 17% in 2h) and complete drug release (the cumulative release degree is 95% in 12 h).
Example 4
(1) Preparing the rhizoma corydalis total alkaloid extract: 150g of rhizoma corydalis decoction pieces are weighed, 12 times of 65% ethanol is added, and reflux extraction is carried out for 3 times, 1.5h each time. Mixing the obtained extractive solutions, concentrating under reduced pressure at 50 deg.C until no alcohol smell exists, centrifuging (7000 rpm at 4 deg.C for 30min), and collecting supernatant to obtain 0.6g crude drug/mL supernatant. Weighing the treated D141 resin (the diameter-height ratio is 1: 9), loading the resin on a column by a wet method, loading 2BV corydalis tuber extracting solution by 2BV/h, standing for 2h, taking 0.2 wt% NaCl of 1.3BV as an impurity removal solvent, wherein the impurity removal speed is 2BV/h, taking 6BV 80% ethanol as an elution solvent, eluting at the speed of 4BV/h, collecting the eluent after discarding the former 0.7BV eluent, concentrating the eluent at 60 ℃ under reduced pressure to form a thick extract, drying at 60 ℃ under normal pressure, and finally drying at 60 ℃ under vacuum to obtain the D141 resin.
(2) Preparing corydalis tuber total alkaloid gastric floating tablets: weighing 15g of the corydalis ambigua total alkaloid extract, 8g of ethyl cellulose, 15g of HPMC K15M 8, 4g of sodium bicarbonate, 4.8g of sodium alginate, 0.124g of silica gel micropowder and 0.25g of magnesium stearate according to a mass ratio, fully and uniformly mixing according to an equivalent incremental method, sieving and uniformly mixing, and directly tabletting powder with the hardness of 3-4 kg/m3 to obtain the corydalis ambigua total alkaloid gastric floating tablets, wherein the weight of each tablet is 2.5 +/-0.125 g.
The gastric floating tablet prepared by the method has the advantages of quick floating, long floating time (more than 12h), stable drug release, no burst release phenomenon (the cumulative release degree is 18% in 2h) and complete drug release (the cumulative release degree is 95% in 12 h).
Example 5
(1) Preparing the rhizoma corydalis total alkaloid extract: 150g of rhizoma corydalis decoction pieces are weighed, 8 times of 60% ethanol is added, and reflux extraction is carried out for 3 times, 2 hours each time. Mixing the obtained extractive solutions, concentrating under reduced pressure at 60 deg.C until no alcohol smell exists, centrifuging (7000 rpm at 4 deg.C for 30min), and collecting supernatant to obtain 0.6g crude drug/mL supernatant. Weighing the treated D141 resin (the diameter-height ratio is 1: 7), loading 2.3BV corydalis tuber extract by 2.5BV/h, standing for 2h, taking 1.3BV ultrapure water as an impurity removal solvent, removing the impurity at the speed of 1.5BV/h, taking 6BV 80% ethanol as an elution solvent, eluting at the speed of 2BV/h, collecting the eluent after discarding the previous 1.5BV eluent, concentrating the eluent at 60 ℃ under reduced pressure to form thick extract, drying at 60 ℃ under normal pressure, and finally drying at 60 ℃ under vacuum to obtain the D141 resin.
(2) Preparing corydalis tuber total alkaloid gastric floating tablets: weighing 15g of the corydalis ambigua total alkaloid extract, 4g of ethyl cellulose, 15g of HPMC K15M 4, 4g of sodium bicarbonate, 4.8g of sodium alginate, 0.124g of silica gel micropowder and 0.25g of magnesium stearate according to a mass ratio, fully and uniformly mixing according to an equivalent incremental method, sieving and uniformly mixing, and directly tabletting powder with the hardness of 3-4 kg/m3 to obtain the corydalis ambigua total alkaloid gastric floating tablets, wherein the weight of each tablet is 2.5 +/-0.125 g.
The gastric floating tablet prepared by the method has the advantages of quick floating, long floating time (more than 12h), stable drug release, no burst release phenomenon (the cumulative release degree is 19% in 2h) and complete drug release (the cumulative release degree is 96% in 12 h).
Example 6
(1) Preparing the rhizoma corydalis total alkaloid extract: 150g of rhizoma corydalis decoction pieces are weighed, 8 times of 60% ethanol is added, and reflux extraction is carried out for 3 times, 2 hours each time. Mixing the obtained extractive solutions, concentrating under reduced pressure at 60 deg.C until no alcohol smell exists, centrifuging (7000 rpm at 4 deg.C for 30min), and collecting supernatant to obtain a supernatant of 0.6g crude drug/mL. Weighing the treated D141 resin (the diameter-height ratio is 1: 7), loading the resin on a column by a wet method, loading 2BV corydalis tuber extracting solution by 2.5BV/h, taking 1.3BV ultrapure water as an impurity removal solvent, carrying out elution at the speed of 2BV/h, taking 6.5BV 95% ethanol as an elution solvent, carrying out elution at the speed of 2BV/h, collecting the eluent after discarding the former 0.7BV eluent, concentrating the eluent at 60 ℃ under reduced pressure to obtain a thick extract, drying at 60 ℃ under normal pressure, and finally drying at 60 ℃ under vacuum to obtain the D141 resin.
(2) Preparing corydalis tuber total alkaloid gastric floating tablets: weighing 15g of the corydalis ambigua total alkaloid extract, 12g of ethyl cellulose, 15g of HPMC K15M 8g, 4g of sodium bicarbonate, 3.2g of sodium alginate, 0.124g of superfine silica gel powder and 0.25g of magnesium stearate according to a mass ratio, fully and uniformly mixing according to an equivalent incremental method, sieving and uniformly mixing, and directly tabletting powder with the hardness of 3-4 kg/m3 to obtain the corydalis ambigua total alkaloid gastric floating tablets, wherein the weight of each tablet is 2.5 +/-0.125 g.
The gastric floating tablet prepared by the method has the advantages of quick floating, long floating time (more than 12h), stable drug release, no burst release phenomenon (the cumulative release degree is 19% in 2h) and complete drug release (the cumulative release degree is 97% in 12 h).
Example 7
(1) Preparing the rhizoma corydalis total alkaloid extract: 150g of rhizoma corydalis decoction pieces are weighed, 8 times of 60% ethanol is added, and reflux extraction is carried out for 3 times, 2 hours each time. Mixing the obtained extractive solutions, concentrating under reduced pressure at 60 deg.C until no alcohol smell exists, centrifuging (7000 rpm at 4 deg.C for 30min), and collecting supernatant to obtain a supernatant of 0.6g crude drug/mL. Weighing the treated D141 resin (the diameter-height ratio is 1: 7), loading the resin on a column by a wet method, loading 2BV corydalis tuber extracting solution by 2.5BV/h, taking 1.3BV ultrapure water as an impurity removal solvent, carrying out elution at the speed of 2BV/h, taking 6.5BV 95% ethanol as an elution solvent, carrying out elution at the speed of 2BV/h, collecting the eluent after discarding the former 0.7BV eluent, concentrating the eluent at 60 ℃ under reduced pressure to obtain a thick extract, drying at 60 ℃ under normal pressure, and finally drying at 60 ℃ under vacuum to obtain the D141 resin.
(2) Preparing corydalis tuber total alkaloid gastric floating tablets: weighing 1.5g of the corydalis tuber total alkaloid extract, 1.2g of ethyl cellulose, 15. 15M 0.8g of HPMC K, 0.4g of sodium bicarbonate, 0.32g of sodium alginate, 0.0124g of micropowder silica gel, 0.025g of magnesium stearate and a proper amount of fluorescent dye according to the mass ratio, fully and uniformly mixing according to an equivalent incremental method, sieving and uniformly mixing, and performing powder direct tabletting to obtain the corydalis tuber total alkaloid gastric floating tablets, wherein the weight of each tablet is 50 mg.
The gastric floating tablet prepared by the method has the advantages of quick floating, long floating time (more than 12h), stable drug release, no burst release phenomenon (the cumulative release degree is 19% in 2h) and complete drug release (the cumulative release degree is 97% in 12 h).
A rat with the weight of about 200g is selected, a fluorescence imaging technology and an X-ray imaging technology are combined, a small gastric floating tablet of the corydalis tuber total alkaloids by a fluorescent dye is marked, and the in vivo retention evaluation of the rat is carried out, and the result shows that the small gastric floating tablet of the corydalis tuber total alkaloids prepared by the method has a good retention effect in vivo, and the retention time can reach 12 hours.
1. And (3) performance testing:
1.1 determination of flotation Properties
Placing rhizoma corydalis total alkaloids gastric floating tablet at 37 + -0.5 deg.C, 900ml0.1mol-1In the hydrochloric acid solution, the stirring speed is 100r.min-1The time to rise and the time to stay to float were observed, and the specific results are shown in Table 1.
Table 1 flotation performance results for examples 1-6
1.2 establishment of method for measuring in vitro release degree of corydalis tuber total alkaloid gastric floating tablet substance group
1.2.1 preparation of stock solutions
Collecting 1 tablet of rhizoma corydalis total alkaloids floating in stomach tablet, precisely weighing, grinding, adding degassing release medium (0.1 mol. L)-1Hydrochloric acid) 900mL, filtering the solution through a 0.45 μm microporous membrane, and collecting the filtrate to obtain stock solution (concentration equivalent to 0.4089 mg. mL)-1)。
1.2.2 detection method
Detecting the gastric floating substance group solution of rhizoma corydalis total alkaloids obtained from each part with ultraviolet-visible spectrophotometer at 0.1mol.L-1Hydrochloric acid is used as a blank contrast, and the blank contrast is scanned within the ultraviolet wavelength range of 220-400 nm,and outputting the absorbance at the wavelength of every 1nm to obtain the ultraviolet determination spectrum of the rhizoma corydalis total alkaloid substance group.
1.2.3 substance group concentration Standard Spectrum
Taking a proper amount of stock solution of the standard substance group, and adding 0.1mol.L-1And (3) taking hydrochloric acid as a blank control, selecting an absorption spectrum of 220-400 nm as a substance group concentration standard spectrum according to the absorption characteristics of the stock solution in the ultraviolet and visible wavelength ranges, and outputting the absorbance at the integral wavelength to obtain the product. And (3) taking the wavelength as an abscissa and the absorbance of each wavelength point as an ordinate to obtain a concentration standard spectrum of the sustained-release tablet substance group. Meanwhile, the blank adjuvant solution of each sustained release tablet is scanned by the same method, as shown in figure 1. The result shows that the blank auxiliary materials are basically free of interference.
1.2.4 Linear relationship
Precisely transferring 1, 2, 3, 5, 7, 10mL of stock solution into 10mL volumetric flasks, respectively adding release medium to dilute to scale, and mixing to obtain 0.0409, 0.0818, 0.1227, 0.2044, 0.2862, 0.4089 mg/mL-1The test solution of (1). Determining an ultraviolet absorption spectrogram of a sample by an Equipped method, calculating by a Kalman filtering method to obtain the concentration of a substance group of each standard solution, and performing least square linear regression on the mass concentration marked by the piece weight and the concentration value of the substance group to obtain a regression equation: Y2.4833X +0.0001 (R)20.9999). The results show that the mass concentration of the sustained-release tablet is 0.0409-0.4089 mg/mL-1The range has good linear relation.
1.2.5 precision investigation
Taking the concentrations of 0.0818, 0.2044 and 0.4089 mg/mL-1The test solutions of (1) were measured 6 times in succession according to the above-mentioned measurement method, and the concentrations of the substance groups of each test solution were calculated. RSD values of the concentrations of the substance groups of the test solution with low, medium and high concentrations are 0.11%, 0.05% and 0.02% respectively, which shows that the precision of the substance group concentration determination method is good.
1.2.6 stability Studies
Taking the concentrations of 0.0818, 0.2044 and 0.4089 mg/mL-1The test solutions of (1) were left at room temperature, sampled for 0, 2, 4, 6, 8, 10, and 12 hours, and the concentrations of the substance groups in the test solutions were calculated by the above-mentioned methods. Low and mediumAnd the RSD values of the substance group concentration of the test solution with the higher concentration of 3 are 0.22%, 0.20% and 0.23% respectively, which shows that the substance group solution of the corydalis tuber total alkaloid gastric floating tablets has good stability within 12 hours.
1.2.7 method for determining substance group release
According to the first method of the four-part release rate measurement method of the 2015 edition pharmacopoeia of the people's republic of China. Dissolution medium: 0.1mol. L-1Hydrochloric acid solution 900mL, medium temperature: (37 ± 0.5) ° c, rotation speed: 100r.min-1And sampling time: 0.5, 1, 2, 4, 6, 8, 10 and 12 h. Sequentially placing corydalis ambigua total alkaloid gastric-floating tablets into 6 dissolution cups, sampling 5mL at a specified time point, then supplementing 5mL of release medium at the same temperature, passing the dissolution liquid through a 0.45-micrometer microporous filter membrane, taking a subsequent filtrate, scanning within a wavelength range of 220-400 nm by taking the release medium as a blank control, outputting absorbance at an integer wavelength, comparing with a substance group concentration standard spectrum, calculating the substance group release degree of the corydalis ambigua total alkaloid gastric-floating tablets in examples 1-6, and the result shows that the corydalis ambigua total alkaloid gastric-floating tablets prepared in examples 1-6 are basically completely released (the release degree is more than 90% in 12h), and the release is stable and has no burst release phenomenon (the release degree is more than 90% in 2h)<20％)。
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (5)
1. A corydalis tuber total alkaloid gastric floating tablet comprises an active component and a pharmaceutic adjuvant, and is characterized in that: the active ingredient is a rhizoma corydalis total alkaloid extract, and the pharmaceutic adjuvant comprises a slow release framework material, a retardant, a bleaching aid and a glidant; the weight ratio of the active ingredients to the pharmaceutical excipients is 1: 1.1-1: 2.1;
the corydalis tuber total alkaloid gastric floating tablet comprises the following components in percentage by weight:
32-47% of corydalis tuber total alkaloid extract;
24-33% of a slow-release framework material;
12-29% of a retarder; the retarder is one or more of ethyl cellulose and acrylic resin;
9-26% of bleaching assistant;
0.8-1.2% of a flow aid;
the preparation method of the rhizoma corydalis total alkaloid extract comprises the following steps:
(1) carrying out reflux extraction on corydalis tuber decoction pieces for 1-3 times by using ethanol with the mass of 8-12 times and the concentration of 55-65wt%, and taking an extracting solution after 1.5-2.5 hours each time;
(2) concentrating the extracting solution at 50-60 ℃ until no alcohol smell exists; then centrifuging for 25-35min at 5000-; taking the supernatant to prepare a sample solution, wherein the concentration of the sample solution is 0.3-0.6 g crude drug/mL;
(3) loading the pretreated macroporous resin into a column, loading the sample, and removing impurities; the column packing method comprises the following steps: filling the column by a wet method with a diameter-height ratio of 1: 5-1: 9, wherein the sample loading amount is 1.5-2.3BV, the sample loading speed is 1.5-2.5 BV/h, and standing for 1-2 h; the impurity removing solvent during impurity removing is one or more of ultrapure water, 0.1-0.3wt% NaCl solution or 8-12wt% ethanol solution; the dosage of the impurity removal solvent is 1.0-1.5 BV, and the impurity removal speed is 1.5-2.5 BV/h;
(4) eluting with an elution solvent, and collecting the eluent after discarding the previous 0.5-1.5BV of the eluent; the elution solvent is 80-95 wt% of ethanol solution, the dosage of the elution solvent is 5.5-6.5 BV, and the elution speed is 2-4 BV/h;
(5) concentrating the eluate, and drying; concentrating the eluent under reduced pressure at 55-65 ℃ until no alcohol smell exists, and then performing spray drying to obtain the eluent; or concentrating the extract under reduced pressure to obtain a thick extract, and then drying the thick extract in vacuum at 50-65 ℃ to obtain the extract; or concentrating under reduced pressure to obtain a thick extract, and drying at the temperature of 55-65 ℃ under normal pressure to obtain the extract;
the main active ingredients in the rhizoma corydalis total alkaloid extract comprise palmatine hydrochloride, dehydrocorydaline, tetrahydropalmatine and corydaline A, and the proportion of the four monomeric alkaloids in the rhizoma corydalis total alkaloid extract is 1: (5.96-7.63): (2.46-2.86): (2.92-3.46).
2. The corydalis tuber total alkaloid gastric floating tablet as claimed in claim 1, wherein the slow release skeleton material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose and sodium alginate.
3. The corydalis tuber total alkaloid gastric floating tablet as claimed in claim 1, wherein the bleaching assistant is one or more of calcium bicarbonate, sodium bicarbonate and magnesium carbonate.
4. The corydalis tuber total alkaloid gastric floating tablet as claimed in claim 1, wherein the glidant is selected from one or more of magnesium stearate, aerosil and talcum powder.
5. The corydalis tuber total alkaloid gastric floating tablet as claimed in one of claims 1 to 4, characterized in that the preparation method comprises the following steps: mixing rhizoma corydalis total alkaloids, sustained release matrix material, retarder, bleaching aid and glidant, and tabletting by conventional method.
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| CN1857421A (en) * | 2006-03-07 | 2006-11-08 | 邹广 | Preparing method of total corydaline extract and corydalis preparation |
| CN103054828A (en) * | 2012-12-26 | 2013-04-24 | 蚌埠丰原涂山制药有限公司 | Ranitidine bismuth citrate intra-gastric floating sustained-release tablet and preparation method thereof |
| CN103191198A (en) * | 2013-04-03 | 2013-07-10 | 中国中医科学院中药研究所 | Rhizoma corydalis extract as well as preparation method and use thereof |
| CN103751115A (en) * | 2013-12-29 | 2014-04-30 | 浙江中医药大学 | Tetrahydropalmatine intra-gastric floating oral microsphere |
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| CN1857421A (en) * | 2006-03-07 | 2006-11-08 | 邹广 | Preparing method of total corydaline extract and corydalis preparation |
| CN103054828A (en) * | 2012-12-26 | 2013-04-24 | 蚌埠丰原涂山制药有限公司 | Ranitidine bismuth citrate intra-gastric floating sustained-release tablet and preparation method thereof |
| CN103191198A (en) * | 2013-04-03 | 2013-07-10 | 中国中医科学院中药研究所 | Rhizoma corydalis extract as well as preparation method and use thereof |
| CN103751115A (en) * | 2013-12-29 | 2014-04-30 | 浙江中医药大学 | Tetrahydropalmatine intra-gastric floating oral microsphere |
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